Process of making barbituric acids.



UNITED sTATEs PATENT oEEioE;

OTTO WOLFES,

OF DARMSTADT, GERMANY. ASSIGNOR TO THE FIRM OF E. MEROK, OF DARMSTADT. GERMANY.

PROCESS OF MAKING- BARBITURIC ACIDS- I Specification of Letters Patent.

Patented March 6, 1906.

. Application filed November 8, 1904. Serial No. 231,873

My invention relates to the manufacture of 1o barbituric acids; and it consists of certain novel processes particularly pointed out in the concluding claims.

From experiments made by Traube, Conrad, and myself it is known that cyanacetic I5 ester and its substitution products may be condensed with urea, guanidin, and similar bodies to derivates of pyrimidin, one amid of the urea, &c., combining with the cyano en group of the ester, while the carboxethy in separating alcohol participates with the second amid of the ring formation. The process is represented by the following equation:

w on NH m co COOR NH/ NH :10 OL NH\ /CO+ROH. y comm It has been discovered by me that compounds with two cyanogen groi1ps-as, for instance, the malonitrilemay be condensed with urea and with compounds constituted in an analogous Wayas, for example, guanidin and the derivatives and homologues of urea and guanidinif condensing means (viz., alkali metals, their amids, or alcoholates) are employed; but even without the em- 0 ployment of such condensing means the combination is successful if the bodies are permitted to act on each other for a prolonged time at a high temperature or under pressure.

My process as outlined above and em.-

bodied in various forms in the following exalcohol.

amples may be expressed by the following formula:

In the above formula R and R indicate hydrogen atoms or simple alkyl radicals, and X indicates a bivalent body, such 'as oxygen and irnino, (NH radical.) The bodies obtained in this way may be easily converted into the corresponding barbituric acids by an agent separating ammonia. Such agent may be sulfuric acid, hydrochloric acid, or nitric acid or even alkalis, (the latter, however, be ing less suitable.)

I will now describe the manner in which I at present prefer to practice my invention, giving, by way of illustration, a number of examples thereof; but it willbe understood that various modifications and changes, both as to materials and treatment, may be made without departing from the spirit of my in- 7 5 vention and Without exceeding the scope of my claims.

First example: A solution of 9.6 kilograms guanidinhydrochlorate (one molecule) in alcohol is mixed with a solution of 2.3 kilograms sodium (one molecule) in fifty liters of alcohol, the separated chlorid of sodium drawn ofi,-and the solution of the free guanidin then heated with 12.2 kilograms (one molecule) diethylmalonitrile for five hours to centigrade. After being cooled off the reactionary mass, fine colorless needles, is drawn OE and carefully Washed with The new product contains alcohol of crystalli'zation and melts at 240centigrade o sulfate or nitrate.-

v wit evaporated.

while foaming up. It is dissolved easily in water and in diluted acids even in the cold. In cold alcohol it can be dissolved only with difficulty. This triiminodiethylbarbituric acid (diiminodiethylmalonyl-guanidin) is converted smoothl into diethylbarbituric acid by being heate for three hours to 120 centigrade with diluted hydrochloric. acid in a closed receptacle. When cooled ofi, the product congeals to a crystalline mass. Separate from the mother-liquor, 'wash with water, and again crystallize from hot water. The thus-purified substance melts at 191 centigrade and has all the properties of the known diethylbarbituric acid.

Second example: 12.2 kilograms dieth lmalonicacidnitrlle are heated with six kil rams urea and 2.3 kilograms sodium in fifty Titers of absolute alcohol for four hours in an autoclave to centigrade. After adding six liters of glacial acetic-acid the alcohol is The residue is heated for an hour with about one hundred liters of water and is then left standing over night. After bein dissolved in two molecules of warm dilute hydrochloric acid and being precipitated with ammonia the base crystallizes in tufted aggregates of crystal. It is a 5-diethyl-2 oxy-4, 6-diiminopyrimidin. melts, while developing basic vapors, at about 272, (277 corr.) The chlorid is dissolved with more difficulty in water than the In alkalis the base issoluble, but not in ammonia. From hot water it ma be ,crystallized over a ain. If boiled five times the amount of thirty per cent. sulfuric acid, it is converted also into diethylbarbituric acid. The purifying and isolating is'done as in the first example.

Third example: 9.4 kilograms monoethylmalonitrile are heated for five hours with an e uivalent amount of guanidin in alcoholic so ution in an autoclave to 100 centigrade. Lustrous small leaves are separated containing alcohol of crystallization. After being crystallized over again from alcohol and being dried at 100 centigrade they melt at 189, (190 corr.) They can be easily dissolved in cold water and hot alcohol. If this compound is heated for several hours in a closed vessel with diluted hydrochloric acid (1 3)'to it is converted into the monoethylbarbituric acid. This acid melts at 194 corr., (Conrad and Guthzeit giving corr.) It reacts and tastes rather strongly acid just as the barbituric acid itself. It dlffers thereb distinctly from the diethylbarbituric aci which tastes bitter and possesses a reaction which is acid only. to a very small degree.

Fourth example: 6.6 kilograms malonitrile are heated to 100 centigrade for one hour in an autoclave with an equivalent amount of guanidin prepared from 9.6 kilograms hydrochlorate and 2.3 kilograms sodium in eighty liters of alcohol. When cooled off, colorless small needles are separated, the amount of which needles is about 6.5 kilograms when dried. The melting-point of this triiminobarbituric acid is 248, (corr. 252.) The base forms with diluted cold mineral acid salts, which are dissolved only with difficulty. With nitrate of sodium and glacial acetic acid a light violet nitroso body is formed at once. It has a remarkable resistance a ainst warm strong sulfuric acid or boiling so ium hydroxid. By prolonged and highly heating it with acids barbituric acid is obtained therefrom.

Having thus fully described my invention, what I claim, and desire to secure by Letters Patent, is-

1. The process of manufacturing a barbituric acid consisting in the condensation of a malonitrile of the general formula R/ \cN with a substance having the general formula Nl'lz NHZ whereby a 4.6 diimino-pyrimidin of the gen eral formula.

' R cNH-NH c c=x R. (JNHNH is produced, the latter being subsequently converted by saponification into a 4-6-dioxypyrimidin.

2. The process of manufacturing a barbituric acid consisting in condensing a malonitrile with a substance of the general formula NH2 xo NHz the iminobarbituric acid and converting barbituric acid by saponifithus formed into cation. 1

The process consisting in-condensing diethylmalonitrile with guanidin with the aid of sodium alcoholate, and subsequently saponifying to produce barbituric acid.

In testimony whereof I have signed my name to this specification in the presence of two subscribing witnesses.

- OTTO WOLFES. Witnesses:

MAX CON-RAD, WALTER HOUSING. 

